The high-throughput screening core will continue to carry out screening of small-molecule libraries against defined targets or phenotypes. Resources of the core at present include more than 250,000 drug-like compounds and smaller collections of purified natural compounds and approved/investigational drugs, and automated instrumentation for high-throughput screening utilizing optical (fluorescence, absorbance, luminescence) assays. Functions of the core include compound storage and handling, assay design and validation, assay execution, and data analysis. Initial optimization of validated 'hits' (compounds with activity against defined targets or phenotypes) is done by screening of commercially purchased compound analogs. Further 'hit-to-lead' development is done in individual projects in consultation with the core. The core has been utilized extensively during the current project with successful identification and characterization of novel modulators of ion transporters and infection. The core will be heavily utilized by 28 ongoing and new CF related projects.